A wide range of physiologically active compounds are thought to produce their effects by concentration within cell membranes. These compounds range from important pain controlling drugs to toxic compounds including those occurring as occupational or environmental contaminants. In spite of its importance, very little is positively known about the factors controlling the concentrations of these compounds in cell membranes. For example, the influence of lipid composition is not in general known though preliminary work indicates it can be marked (Appendix 3). In recent years, work on drug-membrane interactions have made some progress, but some of the most fundamental data required for developing and refining these ideas is not available. Yet its availability would pave the way for a much better understanding of these membrane acting drugs. It is the objective of this work to provide the necessary data to test and extend these new and potentially powerful concepts. The experimental work involves determination of membrane partition coefficients and drug induced membrane volume changes in membranes of controlled composition. Some preliminary data are included to demonstrate the feasibility of the project which involves an extension of the principal investigator's recent work, preprints of which appear in Appendices 1 and 2. The classes of compounds to be studied include general (volatile) anesthetics, barbiturates, alcohols, nerve blocking agents, aliphatic and aromatic hydrocarbons (including the polycyclic carcinogens) and halogenated hydrocarbons. One important objective will be to test at a molecular level the critical volume hypothesis, which states that anesthesia occurs when a hydrophobic region is caused to expand beyond a certain critical amount by the absorption of molecules of an inert substance. The hypothesis is presently based on experiments with intact animals (Appendix 1) and its confirmation at the molecular level would thus have important mechanistic implications.